PROJECT SUMMARY Multiple myeloma (MM) is the second most common hematological malignancy in the United States and is a disease of older adults. Many of myeloma patients have co-existing medical problems including diabetes and dyslipidemia. Peroxisome proliferator-activated receptor (PPAR) agonists including PPARa agonists (the fibrates) and PPARg agonists (the thiazolidinediones) are FDA-approved drugs for the treatment of dyslipidemia and type 2 diabetes and are commonly used in myeloma patients with those conditions. There is a fundamental gap in understanding how PPAR agonists affect the treatment response and outcomes in patients with MM. We have recently demonstrated that PPAR agonists down-regulate the expression of cereblon, an E3 ligase and the direct target of immunomodulatory agents (IMiDs), in myeloma cells. We have further found that co-administration of fenofibrate attenuated the anti-myeloma activity of lenalidomide in vitro and in vivo in myeloma xenograft mouse model. Moreover, myeloma patients treated with IMiDs in the presence of PPAR agonists appeared to have lower very good partial response rate and worse overall survival compared to myeloma patients with similar characteristics but not taking PPAR agonists. Our long- term goal is to improve the care and outcome of patients with MM. The overall objectives in this application are to determine the molecular mechanism through which PPAR agonists regulate cereblon expression and to characterize the effects of concurrent PPAR agonists on IMiD based chemotherapy in myeloma patients. The central hypothesis is that co-administration of PPAR agonists in conjunction with IMiDs has worse outcomes including decreased response, and decreased progression free and overall survival in myeloma patients compared to patients receiving IMiDs without PPAR agonists. The rationale for the proposed study is that the results have the potential to change our practice in treating myeloma patients who also have diabetes and/or dyslipidemia. Our hypothesis will be tested by pursuing two specific aims: Aim 1 is to determine the molecular mechanisms through which PPAR agonists negatively regulate cereblon expression. Chromatin immunoprecipitation assay, luciferase reporter gene assay, and promoter point mutation will be performed. Aim 2 is to determine if PPAR agonists alter the treatment response and outcomes of myeloma patients treated with IMiDs. A retrospective study with immunohistochemical staining of archived bone marrow biopsy samples will be performed. The study is innovative, because it focuses on the novel interaction between PPAR agonists and IMiDs. The research is significant, because it is expected to vertically advance and expand the knowledge of how we treat multiple myeloma patients with diabetes and dyslipidemia, medical conditions commonly co-existing in older demographic.